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Abstract:

To provide a novel 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative, a method for producing the same, and an agro-horticultural
agent and an industrial material protecting agent containing as an active
ingredient the abovementioned
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative.
To be a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative
represented by Formula (I):
##STR00001##
wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5haloalkoxy group, a phenyl group, a cyano group or a nitro
group; n denotes an integer of 0 to 5; when n is not less than 2, Xs may
be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and A denotes a nitrogen atom or a methyne
group.

Claims:

1. A 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative represented
by Formula (I): ##STR00037## wherein X denotes a halogen atom, a
C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group; n denotes an integer of 0
to 5; when n is not less than 2, Xs may be the same or different;
R1, R2, R3, R4 each independently denotes a hydrogen
atom, a halogen atom or a C1-C5 alkyl group; and A denotes a
nitrogen atom or a methyne group.

2. A method for producing a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative represented by Formula (I) comprising reacting an oxirane
derivative represented by Formula (II), which is obtained by
oxiranylating a carbonyl compound represented by Formula (IV), with a
1,2,4-triazole or imidazole compound represented by Formula (III):
##STR00038## wherein X denotes a halogen atom, a C1-C5 alkyl
group, a C1-C5 haloalkyl group, a C1-C5 alkoxy group,
a C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; ##STR00039## wherein X denotes a halogen
atom, a C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group; n denotes an integer of 0
to 5; when n is not less than 2, Xs may be the same or different;
R1, R2, R3, R4 each independently denotes a hydrogen
atom, a halogen atom or a C1-C5 alkyl group; ##STR00040##
wherein M denotes a hydrogen atom or an alkaline metal; and A denotes a
nitrogen atom or a methyne group; ##STR00041## wherein X, N, R1,
R2, R3 and R4 correspond to the X, N, R1, R2,
R3 and R4 as defined in Formula II described above; and A
corresponds to the A as defined in Formula III described above.

3. An agro-horticultural agent and an industrial material protecting
agent containing a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative according to claim 1 represented by Formula (I): ##STR00042##
wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and A denotes a nitrogen atom or a methyne
group.

4. An oxirane derivative represented by Formula (II) as an intermediate
compound for producing the 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative according to claim 1: ##STR00043## wherein X denotes a
halogen atom, a C1-C5 alkyl group, a C1-C5 haloalkyl
group, a C1-C5 alkoxy group, a C1-C5 haloalkoxy
group, a phenyl group, a cyano group or a nitro group; n denotes an
integer of 0 to 5; when n is not less than 2, Xs may be the same or
different; R1, R2, R3, R4 each independently denotes
a hydrogen atom, a halogen atom or a C1-C5 alkyl group.

5. A carbonyl compound represented by Formula (IV) as an intermediate
compound for producing the 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative according to claim 1: ##STR00044## wherein X denotes a
halogen atom, a C1-C5 alkyl group, a C1-C5 haloalkyl
group, a C1-C5 alkoxy group, a C1-C5 haloalkoxy
group, a phenyl group, a cyano group or a nitro group; n denotes an
integer of 0 to 5; when n is not less than 2, Xs may be the same or
different; R1, R2, R3, R4 each independently denotes
a hydrogen atom, a halogen atom or a C1-C5 alkyl group.

6. A 2-(2-haloethyl)cyclopentanone compound represented by Formula (Va)
as an intermediate compound for producing the
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative according to
claim 1: ##STR00045## wherein X denotes a halogen atom, a
C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group; n denotes an integer of 0
to 5; when n is not less than 2, Xs may be the same or different;
R1, R2, R3, R4 each independently denotes a hydrogen
atom, a halogen atom or a C1-C5 alkyl group; and Z1a is a
halogen atom other than a fluorine atom.

7. A 2-(lower alkoxy)alkyl ketoester compound represented by Formula
(XVIII) as an intermediate compound for producing the
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative according to
claim 1: ##STR00046## wherein X denotes a halogen atom, a
C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group; n denotes an integer of 0
to 5; when n is not less than 2, Xs may be the same of different;
R1, R2, R3, R4 each independently denotes a hydrogen
atom, a halogen atom or a C1-C5 alkyl group; and R5 and
R9 each independently denotes a C1-C4 lower alkyl group.

Description:

TECHNICAL FIELD

[0001] The present invention relates to a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative, a method for
producing the same, and an agro-horticultural agent and an industrial
material protecting agent containing such a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative as an active
ingredient.

BACKGROUND ART

[0002] Conventionally, a novel fungicidal compound has been desired in
view of prevention of environmental pollution or drug resistances. For
example, a large number of products, especially fungicides, containing a
triazole groups are known. Triazole fungicides containing cyclopentane
rings are also known, and disclosed for example in Patent Literatures 1
to 4. In addition, Triazole fungicides containing cycloalkyl groups are
also known, and disclosed for example in Patent Literatures 5 and 6.

[0021] Conventionally, an agro-horticultural pesticide having a low
toxicity to humans, capable of being handled safely, and exhibiting an
excellent inhibitory effect on a wide range of plant diseases has been
desired. Also, there has been a need for a plant growth regulator which
regulates the growth of a variety of crops and horticultural plants
whereby exhibiting yield-increasing effects or quality-improving effects,
as well as an industrial material protecting agent which protects an
industrial material from a wide range of hazardous microorganisms which
invades such materials.

[0022] Accordingly, the present invention aims primarily at providing a
novel 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative exhibiting
an excellent agro-horticultural disease controlling effect, a plant
growth regulating effect and an industrial material protecting effect, a
method for producing the same, and an agro-horticultural agent and an
industrial material protecting agent containing the aforementioned
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative as an active
ingredient.

Solution to Problem

[0023] To achieve the aim mentioned above, the invention first provides a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative represented by
Formula (I).

##STR00002##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and A denotes a nitrogen atom or a methyne
group.

[0024] The invention also provides a method for producing a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative represented by
Formula (I) comprising reacting an oxirane derivative represented by
Formula (II), which is obtained by oxiranylating a carbonyl compound
represented by Formula (IV), with a 1,2,4-triazole or imidazole compound
represented by Formula (III).

##STR00003##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group.

##STR00004##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group.

##STR00005##

wherein M denotes a hydrogen atom or an alkaline metal; and A denotes a
nitrogen atom or a methyne group.

##STR00006##

wherein X, N, R1, R2, R3 and R4 correspond to the X,
N, R1, R2, R3 and R4 as defined in Formula II
described above; and A corresponds to the A as defined in Formula III
described above.

[0025] Although it is possible here that an oxirane derivative represented
by Formula (II) which is obtained by oxiranylating a carbonyl compound
represented by Formula (IV), with a 1,2,4-triazole or imidazole compound
represented by Formula (III) is first produced and subsequently reacted
with a 1,2,4-triazole or imidazole compound represented by Formula (III),
a method in which upon the oxiranylation the 1,2,4-triazole or imidazole
compound represented by Formula (III) is allowed to coexist and the
carbonyl compound represented by Formula (IV) is oxiranylated while
reacting the 1,2,4-triazole or imidazole compound represented by Formula
(III) whereby producing a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative represented by Formula (I) is also included.

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and A denotes a nitrogen atom or a methyne
group.

Advantageous Effects of Invention

[0027] According to the invention a novel
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative exhibiting
excellent agro-horticultural fungicidal effect, plant growth regulating
effect, and industrial material protecting effect, a method for producing
the same, and an agro-horticultural agent and an industrial material
protecting agent containing a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative described above
as an active ingredient.

DESCRIPTION OF EMBODIMENTS

[0028] Preferred embodiments of the invention are described below while
referring to Figures. The following embodiments only exemplify the
representatives of the invention and do not restrict the scope of the
invention.

A) 5-Benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative

[0029] A 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative according
to the invention is represented by Formula (I) shown above. The
followings are the details of the
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative according to the
invention.

[0030] In the chemical formula (I) shown above, the X denotes a halogen
atom, a C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group. As used herein, the halogen
atom may for example be a chlorine atom, a fluorine atom, a bromine atom,
and an iodine atom. The C1-C5 alkyl group may for example be a
methyl group, an ethyl group, an n-propyl group, an i-propyl group, an
n-butyl group, an i-butyl group, a s-butyl group, a t-butyl group and the
like. The C1-C5 haloalkyl group may for example be a
trifluoromethyl group, a 1,1,2,2,2-pentafluoroethyl group, a chloromethyl
group, a trichloromethyl group, a bromomethyl group and the like. The
C1-C5 alkoxy group may for example be a methoxy group, an
ethoxy group, an n-propoxy group and the like. The C1-C5
haloalkoxy group may for example be a trifluoromethoxy group, a
difluoromethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, a
2,2,2-trifluoroethoxy group and the like.

[0032] Among the above definitions, the following substituents Xs are
still more preferred; fluorine atom, chlorine atom, bromine atom or
trifluoromethyl group.

[0033] The n is an integer of 0 to 5. When n is not less than 2, Xs may be
the same or different. The n is preferably in the range of 1 to 2. It is
still more preferred that n is 1 and X is bonded to the 4-position.

[0034] The R1, R2, R3, R4 each independently denotes a
hydrogen atom, a halogen atom or a C1-C5 alkyl group. As used
herein, the halogen atom may for example be a chlorine atom, a fluorine
atom, a bromine atom, and an iodine atom. The C1-C5 alkyl group
may for example be a methyl group, an ethyl group, an n-propyl group, an
i-propyl group, an n-butyl group, an i-butyl group, a s-butyl group, a
t-butyl group and the like. Among the above definitions, the following
substituents R1, R2, R3, R4 are more preferred;
hydrogen atom, methyl group or chlorine atom. The following substituents
R1, R2, R3, R4 are still more preferred; hydrogen
atom or methyl group.

[0035] The A denotes a nitrogen atom or a methyne group. A nitrogen atom
is more preferred.

[0036] Depending on the combination of types of the substituents for the
X, R1, R2, R3, R4 and A and numerical values for the
n described above, the compounds shown in Tables 1 to 20 are exemplified
as the 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivatives according
to the invention.

[0037] While a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative
according to the invention may exist as any of the stereoisomers (C-form
and T-form) represented by Formula (I-C) and Formula (I-T) shown below,
either isomer as well as their mixture may be employed. With regard to
the chemical formulae shown below, the relative configuration of one
whose hydroxyl group in the 4-position and benzyl group in the 5-position
are in a cis relationship is designated as (I-C), and the relative
configuration of one whose relevant groups are in a trans relationship is
designated as (I-T).

##STR00008##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and A denotes a nitrogen atom or a methyne
group.

[0038] While in the description shown below in relation to the production
the solvent employed is not limited particularly, those which may be
exemplified include halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like, aromatic hydrocarbons such as
benzene, toluene, xylene and the like, aliphatic hydrocarbons such as
petroleum ether, hexane, methylcyclohexane and the like, amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone
and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane and
the like, alcohols such as methanol, ethanol and the like.

[0039] Those which may also be exemplified are water, carbon disulfide,
acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide and the like.
Two or more of these solvents may be employed in combination.

[0040] One which may also be exemplified is a solvent composition
consisting of solvents which do not form a homogenous layer with each
other. For example, to a reaction mixture, a quaternary ammonium salt
such as tetrabutylammonium salt and a phase transfer catalyst such as a
crown ether and analogues are added to effect the reaction thereof. In
such a case, the solvents employed are not limited, while the oily phase
may consists of benzene, chloroform, dichloromethane, hexane, toluene and
the like.

[0041] In the description shown below in relation to the production, the
reaction may be performed in the presence of a base or an acid in
addition to the solvents described above.

[0042] In such a case, the base employed is not limited particularly, and
may for example be a carbonate of an alkaline metal such as sodium
carbonate, sodium hydrogen carbonate, potassium carbonate, potassium
hydrogen carbonate and the like; a carbonate of an alkaline earth metal
such as calcium carbonate, barium carbonate and the like; a hydroxide of
an alkaline metal such as sodium hydroxide, potassium hydroxide and the
like; an alkoxide of an alkaline metal such as sodium methoxide, sodium
ethoxide, sodium t-butoxide, potassium t-butoxide and the like; an
alkaline metal hydride such as sodium hydride, potassium hydride, lithium
hydride and the like; an organometal compound of an alkaline metal such
as n-butyl lithium and the like; an alkaline metal such as sodium,
potassium, lithium and the like; an alkaline metal amide such as lithium
diisopropyl amide and the like; and an organic amine such as
triethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline,
1,8-diazabicyclo-7-[5.4.0]undecene and the like.

[0043] Also, the acid employed is not limited particularly, it may for
example be an inorganic acid such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid and the like, an organic acid such as
formic acid, acetic acid, butyric acid, p-toluenesulfonic acid and the
like, a Lewis acid such as lithium chloride, lithium bromide, rhodium
chloride and the like.

[0044] A method for producing a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative represented by
Formula (I) described above is now explained below. Scheme (1) is a
scheme illustrating a method for producing a
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative according to the
invention.

##STR00009##

[0045] A 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative
represented by Formula (I) described above is characterized in that an
oxirane derivative represented by Formula (II) described above, which is
obtained by oxiranylating a carbonyl compound represented by Formula (IV)
described above, is reacted with a 1,2,4-triazole or imidazole compound
represented by Formula (III) described above, whereby forming a
carbon-nitrogen bond between the carbon atom in the oxirane ring of the
oxirane derivative described above and the nitrogen atom in the
1,2,4-triazole or imidazole compound (see Scheme (1)).

[0046] A method for obtaining an oxirane derivative represented by Formula
(II) by oxiranylating a carbonyl compound represented by Formula (IV) is
now explained below.

##STR00010##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group.

[0047] A preferred first synthesis method of an oxirane derivative
represented by Formula (II) employed in the invention may for example be
a method in which a carbonyl compound represented by Formula (IV) is
reacted with a sulfur ylide such as a sulfonium methylide including
dimethyl sulfonium methylide or a sulfoxonium methylide including
dimethyl sulfoxonium methylide in a solvent (see Scheme (2)).

##STR00011##

[0048] The sulfonium methylides or sulfoxonium methylides used here can be
produced by reacting a sulfonium salt (for example, trimethyl sulfonium
iodide or trimethyl sulfonium bromide and the like) or a sulfoxonium salt
(for example, trimethyl sulfoxonium iodide or trimethyl sulfoxonium
bromide and the like) with a base in a solvent.

[0049] The amount of the sulfonium methylide or sulfoxonium methylide
employed here is 0.5 to 5 moles, preferably 0.8 to 2 moles per mole of
the carbonyl compound represented by Formula (IV) described above.

[0050] While the solvent employed is not limited particularly, it may for
example be dimethyl sulfoxide, an amide such as N-methylpyrrolidone,
N,N-dimethylformamide, tetrahydrofuran, dioxane and other ethers, as well
as a solvent mixture thereof.

[0051] While the base employed for producing the sulfonium methylide or
sulfoxonium methylide is not limited particularly, those employed
preferably include metal hydrides such as sodium hydride, alkaline metal
alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide,
potassium t-butoxide and the like.

[0052] The reaction temperature of the preferred first synthetic method of
the oxirane derivative represented by Formula (II) described above may
appropriately be selected depending on the types of the solvent, the
carbonyl compound represented by Formula (IV) described above, the
sulfonium salt or sulfoxonium salt, bases employed, and is preferably
-100 degrees C. (Celsius) to 200 degrees C., more preferably -50 degrees
C. to 150 degrees C. The reaction time may appropriately be selected
depending on the types of the solvent, the carbonyl compound represented
by Formula (IV) described above, the sulfonium salt or sulfoxonium salt,
bases employed, and is preferably 0.1 hour to several days, more
preferably 0.5 hours to 2 days.

[0053] As a preferred second synthesis method of the oxirane derivative
represented by Formula (II) employed in the invention, a method in which
the carbonyl compound represented by Formula (IV) described above is
reacted with samarium diiodide and diiodomethane in a solvent and then
treated with a base may be exemplified. The base employed is not limited
particularly, and may for example be sodium hydroxide (see Scheme (3)).

##STR00012##

[0054] The amount of samarium diiodide employed here is preferably 0.5 to
10 moles, more preferably 1 to 6 moles per mole of the carbonyl compound
represented by Formula (IV) described above. The amount of diiodomethane
employed here is preferably 0.5 to 10 moles, more preferably 0.8 to 5
moles per mole of the carbonyl compound represented by Formula (IV)
described above.

[0055] Samarium diiodide employed here can be produced by reacting an
elemental samarium with 1,2-diiodoethane or diiodomethane in an anhydrous
solvent.

[0056] While the amount of samarium diiodide per mole of the carbonyl
compound represented by Formula (IV) described above is not limited
particularly, it is preferably 0.5 to 10 moles, more preferably 0.8 to 6
moles. The preferred solvent employed in this reaction is not limited
particularly, and it may for example be an ether such as tetrahydrofuran
and the like.

[0057] The reaction temperature of the preferred second synthetic method
of the oxirane derivative represented by Formula (II) described above may
appropriately be selected depending on the types of the solvent, the
carbonyl compound represented by Formula (IV) described above, the base
employed, and is preferably -100 degrees C. to 150 degrees C., more
preferably -50 degrees C. to 100 degrees C. The reaction time may
appropriately be selected depending on the types of the solvent, the
carbonyl compound represented by Formula (IV) described above, the base
employed, and is preferably 0.1 hour to several days, more preferably 0.5
hours to 2 days.

[0058] A method for obtaining an
5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative by reacting an
oxirane derivative represented by Formula (II) described above with a
1,2,4-triazole or imidazole compound represented by Formula (III)
described above is now explained below.

[0059] It is preferred to mix an oxirane derivative represented by Formula
(II) described above with a 1,2,4-triazole or imidazole compound
represented by Formula (III) described above in a solvent to form a
carbon-nitrogen bond between the carbon atom in the oxirane ring of the
oxirane derivative and the nitrogen atom in the 1,2,4-triazole or
imidazole compound (see Scheme (4)).

##STR00013##

[0060] While the solvent employed here is not limited particularly, it may
for example be an amide such as N-methylpyrrolidone or
N,N-dimethylformamide.

[0061] The amount of the compound represented by Formula (III) per mole of
the oxirane derivative represented by Formula (II) is usually 0.5 to 10
moles, preferably 0.8 to 5 moles. It is possible to add a base if
necessary, and in such a case the amount of the base per the compound
represented by Formula (III) is usually greater than 0 up to 5 moles,
preferably 0.5 to 2 moles.

[0062] The reaction temperature may appropriately be selected depending on
the solvent and the base employed, and is preferably 0 degrees C. to 250
degrees C., more preferably 10 degrees C. to 200 degrees C. The reaction
time may appropriately be selected depending on the solvent and the base
employed, and is preferably 0.1 hour to several days, more preferably 0.5
hours to 2 days.

[0063] While there is a method in which an oxirane derivative represented
by Formula (II) is produced and then reacted stepwise with a compound
represented by Formula (III), the yield may be reduced due for example to
generation of byproducts such as an oxetane derivative when the
oxiranylating reaction is conducted alone in the method described above
as a preferred first synthesis method of an oxirane derivative
represented by Formula (II) in which a carbonyl compound represented by
Formula (IV) is reacted with a sulfur ylide such as a sulfonium methylide
including dimethyl sulfonium methylide or a sulfoxonium methylide
including dimethyl sulfoxonium methylide in a solvent. In such a case, a
method in which the azolation is conducted while producing the oxirane
derivative represented by Formula (II) is preferred (see Scheme (5)).

##STR00014##

[0064] In such a case, a carbonyl compound represented by Formula (IV)
described above and an azole compound represented by Formula (III) are
dissolved in an amide bond-carrying polar solvent or dimethyl sulfoxide,
or a solvent mixture of such a polar solvent with a selected alcohol, to
which a trimethyl sulfonium salt or a trimethyl sulfoxonium salt and a
base are added intermittently, whereby effecting an in situ generation of
a sulfonium methylide including dimethyl sulfonium methylide or a
sulfoxonium methylide including dimethyl sulfoxonium methylide whereby
accomplishing the azolation while generating the oxirane derivative
represented by Formula (II).

[0065] The solvent employed is not limited particularly, and one employed
preferably may for example be an amide bond-carrying polar solvent such
as N-methylpyrrolidone or N,N-dimethylformamide, or dimethyl sulfoxide,
or a solvent mixture of such a polar solvent with a selected alcohol such
as t-butanol.

[0066] The base employed for producing a sulfonium methylide and a
sulfoxonium methylide is not limited particularly, and one employed
preferably may for example be a metal hydride such as sodium hydride, and
an alkoxide of an alkaline metal such as sodium methoxide, sodium
ethoxide, sodium t-butoxide, potassium t-butoxide and the like. An
alkaline metal salt of 1,2,4-triazole and imidazole may also be employed.

[0067] The reaction temperature of the synthesis method in which a
carbonyl compound represented by Formula (IV) described above and an
azole compound represented by Formula (III) are dissolved in an amide
bond-carrying polar solvent or dimethyl sulfoxide, or a solvent mixture
of such a polar solvent with a selected alcohol, to which a trimethyl
sulfonium halide or a trimethyl sulfoxonium halide and a base are added
intermittently whereby accomplishing the azolation while generating the
oxirane derivative represented by Formula (II) may appropriately be
selected depending on the types of the solvent, the carbonyl compound
represented by Formula (IV) described above, the sulfonium salt or
sulfoxonium salt, bases employed, and is preferably -100 degrees C. to
250 degrees C., more preferably -50 degrees C. to 200 degrees C. The
reaction time may appropriately be selected depending on the types of the
solvent, the carbonyl compound represented by Formula (IV) described
above, the sulfonium salt or sulfoxonium salt, bases employed, and is
preferably 0.1 hour to several days, more preferably 0.5 hours to 2 days.
The number of times the trimethyl sulfonium halide or the trimethyl
sulfoxonium halide and the base are added intermittently is not limited
particularly as long as a certain purpose is achieved, and may usually be
2 to 20 times, preferably 3 to 15 times.

[0068] In such a case, the total amount of the sulfonium salt or
sulfoxonium salt is preferably 0.5 to 5 moles, more preferably 0.8 to 2
moles per the carbonyl compound represented by Formula (IV) described
above. The amount of the compound represented by Formula (III) per mole
of the carbonyl compound represented by Formula (IV) is usually 0.5 to 10
moles, preferably 0.8 to 5 moles. It is further preferred to use a
compound represented by Formula (III) in which the M is an alkaline
metal.

[0069] A method for producing a certain azolylmethylcycloalkanol
derivative in which the azolation is conducted while generating an
oxirane derivative is described in JP-A 1-301664.

[0070] As a preferred first synthesis method of a carbonyl compound
represented by Formula (IV) described above, a method in which a
2-(2-haloethyl)cyclopentanone compound represented by Formula (V) is
subjected to an intramolecular nucleophilic substitution reaction in a
solvent in the presence of a base may be exemplified (see Scheme (6)).

##STR00015##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and Z1 denotes a halogen atom.

##STR00016##

[0071] The base employed here is not limited particularly, and may for
example be an alkaline metal hydride such as sodium hydride and the like,
an alkaline metal carbonate such as sodium carbonate, potassium carbonate
and the like, and an alkaline metal hydroxide such as sodium hydroxide,
potassium hydroxide and the like.

[0072] The reaction temperature of the preferred first synthetic method of
the carbonyl compound represented by Formula (IV) described above may
appropriately be selected depending on the solvent and the base employed,
and is preferably -50 degrees C. to 250 degrees C., more preferably 0
degrees C. to 150 degrees C. The reaction time may appropriately be
selected depending on the solvent and the base employed, and is
preferably 0.1 hour to several days, more preferably 0.5 hours to 2 days.

[0073] As a preferred first synthesis method of a
2-(2-haloethyl)cyclopentanone compound represented by Formula (V)
described above, a method comprising a step in which a ketoester compound
represented by Formula (VII) and a dihalogenoalkane compound represented
by Formula (VIII) are reacted to obtain a haloalkylated ketoester
compound represented by Formula (VI) (hereinafter referred to as Step A)
and a step in which an alkoxycarbonyl group is hydrolyzed and
decarboxylated (hereinafter referred to as Step B) may be exemplified
(see Scheme (7)).

##STR00017##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; and R5 denotes a C1-C4
alkyl group.

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; R5 denotes a C1-C4 alkyl group; and
Z1 denotes a halogen atom.

##STR00020##

[0074] Step A is conducted by reacting the ketoester compound represented
by Formula (VII) and the dihalogenoalkane compound represented by Formula
(VIII) in a solvent in the presence of a base.

[0075] The base employed here is not limited particularly, and may for
example be an alkaline metal hydride such as sodium hydride and the like,
an alkaline metal carbonate such as sodium carbonate, potassium carbonate
and the like. The amount of the base employed is preferably 0.5 to 5
moles, more preferably 0.8 to 2 moles per the ketoester compound
represented by Formula (VII).

[0076] The amount of the dihalogenoalkane compound represented by Formula
(VIII) described above is preferably 0.5 to 10 moles, more preferably 0.8
to 5 moles per mole of the ketoester compound represented by Formula
(VII).

[0077] In the ketoester compound represented by Formula (VII) described
above, R5 is preferably a methyl group or an ethyl group. This
ketoester compound can be synthesized by a known method such as one
described in JP-A 5-78282 (corresponding to EP0537909 etc.). Compounds
(VI) in which X=4-Cl, n=1, R1=H, R2=H, R3=H, R4=H,
Z1=F and Compounds (V) in which X=4-Cl, n=1, R1=H, R2=H,
R3=H, R4=H, Z1=F are described in JP-A 2-72176.

[0078] The reaction temperature of Step A may appropriately be selected
depending on the solvent, the ketoester compound represented by Formula
(VII) described above, the dihalogenoalkane compound represented by
Formula (VIII) described above, and the base employed, and is preferably
0 degrees C. to 250 degrees C., more preferably room temperature to 150
degrees C. The reaction time may appropriately be selected depending on
the solvent, the ketoester compound represented by Formula (VII)
described above, the dihalogenoalkane compound represented by Formula
(VIII) described above, and the base employed, and is preferably 0.1 hour
to several days, more preferably 0.5 hours to 24 hours.

[0079] Step B is conducted by subjecting an alkoxycarbonyl group of the
haloalkylated ketoester compound represented by Formula (VI) described
above to a hydrolysis/decarboxylation in a solvent under an acidic
condition.

[0080] The acid employed here is not limited particularly, and is
preferably an inorganic acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid and the like. The solvent employed is not limited
particularly, and may be water with or without an organic acid such as
acetic acid.

[0081] The reaction temperature of Step B may appropriately be selected
depending on the solvent, the haloalkylated ketoester compound
represented by Formula (VI) described above, and the acid catalyst
employed, and is preferably 0 degrees C. to reflux temperature, more
preferably room temperature to reflux temperature. The reaction time may
appropriately be selected depending on the solvent, the haloalkylated
ketoester compound represented by Formula (VI) described above, and the
acid catalyst employed, and is preferably 0.1 hour to several days, more
preferably 0.5 hours to 24 hours.

[0082] As a preferred second synthesis method of the carbonyl compound
represented by Formula (IV) described above, a method comprising a step
in which a cyclopentanone compound represented by Formula (X) and a
compound represented by Formula (XI) are subjected to an aldol
condensation reaction to obtain an alkylidene compound represented by
Formula (IX) (hereinafter referred to as Step C) followed by a step in
which a carbon-carbon double bond is subjected to a cyclopropanation
(hereinafter referred to as Step D) may be exemplified (see Scheme (8)).

##STR00021##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different.

##STR00022##

wherein R6, R7 each denotes a hydrogen atom or a
C1-C5 alkyl group.

##STR00023##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different: and R6, R7 each denotes a
hydrogen atom or a C1-C5 alkyl group.

##STR00024##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R6, R7 each denotes a hydrogen
atom or a C1-C5 alkyl group; and R1a, R2a each
denotes a hydrogen atom, a halogen atom or C1-C5 alkyl group.

[0083] Step C is conducted by subjecting the cyclopentanone compound
represented by Formula (X) described above and the compound represented
by Formula (XI) described above to an aldol condensation reaction in a
solvent in the presence of a base or an acid.

[0084] The base or acid employed here is not limited particularly, and may
preferably be an alkaline metal hydroxide such as sodium hydroxide,
potassium hydroxide and the like. The amount of the base or acid employed
is preferably 0.01 to 5 moles, more preferably 0.1 to 2 moles per mole of
the cyclopentanone compound represented by Formula (X) described above.

[0085] The amount of the compound represented by Formula (XI) described
above is preferably 0.5 to 10 moles, more preferably 0.8 to 5 moles per
mole of the cyclopentanone compound represented by Formula (X) described
above.

[0086] The cyclopentanone compound represented by Formula (X) described
above can be synthesized by a method described in references.

[0087] The reaction temperature of Step C may appropriately be selected
depending on the solvent, the cyclopentanone compound represented by
Formula (X) described above, the compound represented by Formula (XIII)
described above, and the base or acid employed, and is preferably 0
degrees C. to 250 degrees C., more preferably room temperature to 150
degrees C. The reaction time may appropriately be selected depending on
the solvent, the cyclopentanone compound represented by Formula (X)
described above, the compound represented by Formula (XIII) described
above, and the base or acid employed, and is preferably 0.1 hour to
several days, more preferably 0.5 hours to 24 hours.

[0088] In Step D, the cyclopropanation of the carbon-carbon double bond of
the alkylidene compound represented by Formula (IX) is conducted for
example by (a) reaction with a sulfoxonium ylide such as dimethyl
sulfoxonium methylide, (b) reaction of a trihalomethane for example with
chloroform and a base such as aqueous solution of sodium hydroxide, or
addition reaction of a halocarbene generated by trihaloacetate pyrolysis
and the like, or (c) addition reaction of a hydrocarbon-based carbene
employing diiodomethane and zinc-copper, diiodomethane and diethylzinc
and the like.

[0089] When using (a) reaction with a sulfoxonium ylide, for example, the
amount of the sulfoxonium ylide employed may appropriately be selected
depending on the types of the alkylidene compound represented by Formula
(IX) described above, and is preferably 0.05 to 5 moles, more preferably
0.8 to 2 moles per mole of the alkylidene compound represented by Formula
(X) described above. When the resultant compound (IVa) undergoes here a
reaction with the sulfoxonium ylide under the same condition, an
approximately equivalent amount is preferred for the purpose of obtaining
the resultant compound (IVa) at a high yield.

[0090] The sulfoxonium ylide described above can be produced for example
by reaction of a sulfoxonium salt such as trimethylsulfoxonium iodide or
trimethylsulfoxonium bromide and a base.

[0091] The base employed here is not limited particularly, and may for
example be an alkaline metal hydride such as sodium hydride and the like,
and an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide,
potassium t-butoxide and the like.

[0092] The reaction temperature of Step D may appropriately be selected
depending on the types of the solvent, the alkylidene compound
represented by Formula (IX) described above employed, and is preferably
-100 degrees C. to 150 degrees C., more preferably -20 degrees C. to 100
degrees C. The reaction time may appropriately be selected depending on
the types of the solvent, the alkylidene compound represented by Formula
(IX) described above employed, and is preferably 0.1 hour to several
days, more preferably 0.5 hours to 2 days.

[0093] In a preferred third synthesis method of the carbonyl compound
represented by Formula (IV) described above, a method in which a
spiro[2.]4]heptan-4-one compound represented by Formula (XV) is reacted
with a compound represented by Formula (XVI) in the presence of a base to
obtain a ketoester compound represented by Formula (XIV) (hereinafter
referred to as Step E), and then a carbon-carbon bond is formed between
the carbon atom to which an alkoxycarbonyl group of Compound (XIV) is
bound and the carbon atom to which a halogen atom of a benzyl halide
compound represented by Formula (XIII) to give a benzyl ketoester
compound represented by Formula (XII) (hereinafter referred to as Step
F), and then a hydrolysis/decarboxylation is conducted (hereinafter
referred to as Step G) may be conducted (see Scheme (9)).

wherein Z3 denotes a halogen atom; X denotes a halogen atom, a
C1-C5 alkyl group, a C1-C5 haloalkyl group, a
C1-C5 alkoxy group, a C1-C5 haloalkoxy group, a
phenyl group, a cyano group or a nitro group; n denotes an integer of 0
to 5; when n is not less than 2, Xs may be the same or different.

##STR00029##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and R8 denotes a C1-C5 alkyl
group.

##STR00030##

[0094] The reaction here to obtain Compound (XIV) by reacting Compound
(XV) with Compound (XVI) in the presence of a base may be conducted in a
solvent (step E), and if the Y is a C1-C5 alkoxy group then
Compound (XVI) can be employed as a solvent.

[0095] The amount of Compound (XVI) employed is usually 0.5 to 20 moles,
preferably 0.8 to 10 moles per mole of Compound (XV).

[0096] The base employed here preferably may for example be, but not
limited to, an alkaline metal hydride such as sodium hydride and the
like, and an alkaline metal alkoxide such as sodium methoxide, sodium
ethoxide, potassium t-butoxide and the like. The amount of the base is
usually 0.5 to 5 moles, preferably 0.8 to 2 moles per mole of Compound
(X). The reaction temperature is usually 0 degrees C. to 250 degrees C.,
preferably room temperature to 150 degrees C., and the reaction time is
usually 0.1 hour to several days, preferably 0.5 hours to 24 hours.

[0097] A cyclopentanone compound represented by Compound (XV) employed
here can be synthesized by a method known in references.

[0098] The reaction in which a carbon-carbon bond is formed between the
carbon atom to which an alkoxycarbonyl group of Compound (XIV) is bound
and the carbon atom to which a halogen atom of Compound (XIII) is bound
to give Compound (XII) (Step F) is conducted in a solvent in the presence
of a base.

[0099] The amount of Compound (XIII) employed is usually 0.5 to 10 moles,
preferably 0.8 to 5 moles per mole of Compound (XIV).

[0100] The base employed here preferably may for example be, but not
limited to, an alkaline metal hydride such as sodium hydride and the
like, and an alkaline metal carbonate such as sodium carbonate, potassium
carbonate and the like.

[0101] The amount of the base is usually 0.5 to 5 moles, preferably 0.8 to
2 moles per mole of Compound (XIV).

[0102] The reaction temperature is usually 0 degrees C. to 250 degrees C.,
preferably room temperature to 150 degrees C., and the reaction time is
usually 0.1 hour to several days, preferably 0.5 hours to 24 hours.

[0103] The reaction in which the hydrolysis/decarboxylation of the
alkoxycarbonyl group of Compound (XII) obtained in the reaction described
above is conducted (Step G) may be conducted in a solvent under a basic
or acidic condition, preferably under a basic condition.

[0104] When the hydrolysis is conducted here under a basic condition, the
base is usually an alkaline metal base such as sodium hydroxide,
potassium hydroxide and the like. The solvent is usually water, or water
combined for example with an alcohol.

[0105] When the hydrolysis is conducted here under an acidic condition, an
inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid
and the like is employed preferably as an acid catalyst, and the solvent
is usually water, or water combined with an organic acid such as acetic
acid.

[0106] The reaction temperature is usually 0 degrees C. to reflux
temperature, preferably room temperature to reflux temperature. The
reaction time is usually 0.1 hour to several days, preferably 0.5 hours
to 24 hours.

[0107] As a preferred second synthesis method of a
2-(2-haloethyl)cyclopentanone compound represented by Formula (V)
described above, a method comprising a step in which a ketoester compound
represented by Formula (VII) and a 2-(lower alkoxy)alkyl halide compound
represented by Formula (XVII) are reacted to obtain a 2-(lower
alkoxy)alkylketoester compound represented by Formula (XVIII)
(hereinafter referred to as Step H) followed by a step in which the
alkoxycarbonyl group is hydrolyzed/decarboxylated while replacing the
lower alkoxy group with a halogen atom to obtain a
2-(2-haloethyl)cyclopentanone compound represented by Formula (Va)
(hereinafter referred to as Step I) may be exemplified (see Scheme (10)).

##STR00031##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxy group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; and R5 denotes a C1-C4
alkyl group.

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxyl group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; R5, R9 each independently denotes
a C1-C4 lower alkyl group, and both of R5 and R9 are
preferably methyl groups, ethyl groups, with methyl groups being
preferred especially.

##STR00034##

wherein X denotes a halogen atom, a C1-C5 alkyl group, a
C1-C5 haloalkyl group, a C1-C5 alkoxyl group, a
C1-C5 haloalkoxy group, a phenyl group, a cyano group or a
nitro group; n denotes an integer of 0 to 5; when n is not less than 2,
Xs may be the same or different; R1, R2, R3, R4 each
independently denotes a hydrogen atom, a halogen atom or a
C1-C5 alkyl group; and Z5 denotes a halogen atom,
preferably a bromine atom, a chlorine atom, with a bromine atom being
preferred especially.

##STR00035##

[0108] Step H is conducted by reacting the ketoester compound represented
by Formula (VII) described above and the 2-(lower alkoxy)alkyl halide
compound represented by Formula (XVII) described above in a solvent in
the presence of a base.

[0109] The base employed here is not limited particularly and may for
example be an alkaline metal hydride such as sodium hydride and the like,
and an alkaline metal carbonate such as sodium carbonate, potassium
carbonate and the like. The amount of the base is usually 0.5 to 5 moles,
preferably 0.8 to 2 moles per mole of the ketoester compound represented
by Formula (VII) described above.

[0110] The amount of the 2-(lower alkoxy)alkyl halide compound represented
by Formula (XVII) described above employed is 0.5 to 10 moles, preferably
0.8 to 5 moles per mole of the ketoester compound represented by Formula
(VII) described above.

[0111] The reaction temperature of Step H may appropriately be selected
depending on the types of the solvent, the ketoester compound represented
by Formula (VII) described above, the 2-(lower alkoxy)alkyl halide
compound represented by Formula (XVII) described above, bases employed,
and is preferably 0 degrees C. to 250 degrees C., more preferably room
temperature to 150 degrees C. The reaction time may appropriately be
selected depending on the types of the solvent, the ketoester compound
represented by Formula (VII) described above, the 2-(lower alkoxy)alkyl
halide compound represented by Formula (XVII) described above, bases
employed, and is preferably 0.1 hour to several days, more preferably 0.5
hours to 24 hours.

[0112] Step I is conducted by subjecting the 2-(lower alkoxy)lated
ketoester compound represented by Formula (VI) described above to
hydrolysis/decarboxylation under an acidic condition while replacing the
2-(lower alkoxy) with a halogen atom.

[0113] The acid employed here is not limited particularly, and it is
preferred to use a hydrohalic acid such as hydrobromic acid, hydrochloric
acid and the like since the reaction system should have a halogen atom
for replacing the 2-(lower alkoxy) with a halogen atom. The solvent
employed is not limited particularly, and may be water with or without an
organic acid such as acetic acid.

[0114] The reaction temperature of Step I may appropriately be selected
depending on the solvent, the 2-(lower alkoxy)lated ketoester compound
represented by Formula (XVIII) described above, and the acid catalyst
employed, and is preferably 0 degrees C. to reflux temperature, more
preferably room temperature to reflux temperature. The reaction time may
appropriately be selected depending on the solvent, the 2-(lower
alkoxy)lated ketoester compound represented by Formula (XVIII) described
above, and the acid catalyst employed, and is preferably 0.1 hour to
several days, more preferably 0.5 hours to 24 hours.

[0115] Since an inventive 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative represented by Formula (I) described above has a
1,2,4-triazolyl group or imidazolyl group, it forms an acid addition salt
of an inorganic or organic acid, as well as a metal complex. Accordingly,
it can be used, while constituting a part of such an acid addition salt
or a metal complex, as an active ingredient of an agro-horticultural
agent and an industrial material protecting agent.

[0116] On the other hand, the 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative represented by Formula (I) has at least two asymmetric carbon
atom. Accordingly, it may exist as a mixture of stereoisomers, as a
mixture of optical isomers, as either stereoisomer or optical isomer, the
invention is not limited to any of the mixture of stereoisomers, the
mixture of optical isomers, the stereoisomer or the optical isomer. Thus,
at least one of these stereoisomers or optical isomers can be used as an
active ingredient of an agro-horticultural agent and an industrial
material protecting agent.

[0117] The usefulness of a 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol
derivative represented by Formula (I) according to the invention as an
active ingredient of an agro-horticultural agent and an industrial
material protecting agent is explained below.

[0120] Moreover, the inventive Compound (I) exhibits an excellent ability
of protecting an industrial material from a broad spectrum of hazardous
microorganisms which invade such a material. Examples of such
microorganisms are listed below.

[0122] While an inventive compound may be applied, as an active ingredient
of an agro-horticultural pesticide, alone without any other components,
it is usually combined with a solid carrier, a liquid carrier, a
surfactant, other formulation auxiliary agents to be formulated into
various formulations such as a powder, wettable powder, granule,
emulsifiable concentrate and the like. Such a formulation is formulated
so that it contains the inventive compound as an active ingredient in an
amount of 0.1 to 95% by weight, preferably 0.5 to 90% by weight, more
preferably 2 to 80% by weight. Examples of carriers, diluents and
surfactants employed as formulation auxiliary agents are solid carriers
including talc, kaolin, bentonite, diatomaceous earth, white carbon, clay
and the like, liquid carriers including water, xylene, toluene,
chlorobenzene, cyclohexane, cyclohexanone, dimethyl sulfoxide, dimethyl
formamide, alcohols and the like. The surfactant may appropriately
selected for an intended effect, and the emulsifier may for example be
polyoxiethylene alkylaryl ether, polyoxyethylene sorbitan monolaurate.
The dispersing agent may for example be lignin sulfonate,
dibutylnaphthalene sulfonate and the like, and the wetting agent may for
example be an alkyl sulfonate, alkylphenyl sulfonate and the like. The
formulation described above may be used as it is, or used as being
diluted in a diluent such as water to a certain concentration. The
concentration of the inventive compound when used as being diluted is
preferably 0.001 to 1.0%. The amount of the inventive compound for 1 ha
of the agro-horticultural field such as a farm, paddy field, orchard,
greenhouse and the like is 20 to 5000 g, more preferably 50 to 2000 g.
Since these concentration and amount to be used may vary depending on the
dosage form, time of use, method of use, place of use, subject crop and
the like, it is a matter of course that they can be increased or
decreased regardless of the ranges mentioned above. In addition, the
inventive compound can be used in combination with other active
ingredients, such as fungicides, bactericides, insecticides, acaricides,
herbicides and the like.

[0123] For example, by mixing with the agents listed below, the
performance of an agro-horticultural agent can be enhanced.

[0127] While an inventive compound (I) may be applied, as an active
ingredient of an industrial material protecting agent, alone without any
other components, it is generally dissolved or dispersed in a suitable
liquid carrier, or mixed with a solid carrier, and combined if necessary
with emulsifier, dispersing agent, spreading agent, penetrating agent,
wetting agent, stabilizer and the like and formulated into a dosage form
such as wettable powder, powder, granule, tablet, paste, suspension,
spray and the like. It may also be supplemented with other fungicides,
bactericides, insecticides, deterioration-preventing agent and the like.

[0129] When the inventive compound (I) is contained as an active
ingredient in a formulation, it is added in such an amount that the
concentration becomes 0.1 to 99.9% by weight, although the content may
vary depending on the dosage form and the purpose of use. Upon being used
practically, it is combined appropriately with a solvent, diluent,
extender and the like so that the treatment concentration is usually
0.005 to 5% by weight, preferably 0.01 to 1% by weight.

EXAMPLES

[0130] The invention is embodied below with referring to Production
Examples, Formulation Examples, and Experiment Examples. The invention is
not restricted to the following Production Examples, Formulation
Examples, and Experiment Examples unless departing from its scope.

[0131] Under nitrogen flow, 606 sodium hydride (246 mg, 6.1 mmol) was
washed with hexane, and then suspended in DMSO (2 ml), and
trimethylsulfonium iodide (1.28 g, 6.1 mmol) was added. After stirring at
room temperature for 5 minutes, while cooling with ice, a DMSO (2 ml)
solution of 5-(4-chlorobenzyl)-4-spiro[2.4]heptanone (Compound (IV),
X=4-Cl, n=1, R1=H, R2=H, R3=H, R4=H) (961 mg, 4.1
mmol) was added, and stirring was continued at room temperature for 16
hours. The reaction solution was poured into iced water, and extracted
with ethyl acetate. The organic layer was washed with water, saturated
brine, and dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and a crude title compound was obtained.

[0142] 5-(4-Chlorobenzyl)-4-spiro[2.4]heptanone (Compound (IV), X=4-Cl,
n=1, R1=H, R2=H, R3=H, R4=H) (94.0 g, 400 mmol) was
added together with NMP (20 ml). At about 120 degrees C. and over about 3
hours, t-BuONa (23.14 g, 240 mmol) and trimethyl sulfoxonium bromide
(88.4 g, 511 mmol) were added intermittently in portions, independently.
After completing the addition followed by stirring at the same
temperature for 1 hour, water was added and extraction was made with
water. The organic layer was washed with water, saturated brine, and
dried over anhydrous sodium sulfate. The crude title compound was
obtained. A quantitative analysis of the crude title compound revealed
the production at the yield shown below.

[0147] Under nitrogen flow, 60% sodium hydride (189 mg, 4.7 mmol) was
washed with hexane, and then suspended in DMSO (3 ml), trimethylsulfonium
iodide (983 mg, 4.7 mmol) was added. After stirring at room temperature
for 5 minutes, while cooling with ice, a DMSO (2 ml) solution of
5-(3-chlorobenzyl)-4-spiro[2.4] heptanone (Compound (IV), X=3-Cl, n=1,
R1=H, R2=H, R3=H, R4=H) (739 mg, 3.2 mmol) was added,
and stirring was continued for 6.5 hours at room temperature. The
reaction solution was poured into an iced water, and extracted with ethyl
acetate. The organic layer was washed with water, saturated brine, and
dried over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and a crude title compound was obtained.

[0149] Under nitrogen flow, 60% sodium hydride (120 mg, 3.0 mmol) was
washed with hexane, and then suspended in anhydrous DMF (2 ml), and then
while cooling with ice 1H-1,2,4-triazole (208 mg, 3.0 mmol) was added.
After stirring at room temperature for 5 minutes, an anhydrous DMF (2 ml)
solution of 9-(3-chlorobenzyl)-1-oxadispiro[2.0.2.3]nonane (Compound
(II), X=3-Cl, n=1, R1=H, R2=H, R3=H, R4=H) (748 mg,
3.0 mmol) was added, and stirring was continued for 4 hours at 120
degrees C. The reaction solution was poured into an iced water, and
extracted with ethyl acetate. The organic layer was washed with water,
saturated brine, and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resultant crude product was
purified by silica gel column chromatography (eluent, hexane-ethyl
acetate, 1:1) to obtain the title compound.

[0156] Under nitrogen flow, 60% sodium hydride (178 mg, 4.5 mmol) was
washed with hexane, and then suspended in DMSO (3 ml), and
trimethylsulfonium iodide (929 mg, 4.5 mmol) was added. After stirring at
room temperature for 5 minutes, while cooling with ice, a DMSO (3 ml)
solution of 5-(4-fluorobenzyl)-4-spiro[2.4]heptanone (Compound (IV),
X=4-F, n=1, R1=H, R2=H, R3=H, R4=H) (649 mg, 3.0
mmol) was added, and stirring was continued at room temperature for 12
hours. The reaction solution was poured into an iced water, and extracted
with ethyl acetate. The organic layer was washed with water, saturated
brine, and dried over anhydrous sodium sulfate. The solvent was distilled
of under reduced pressure, and a crude title compound was obtained.

[0165] Under argon flow, samarium (powder, -20 mesh, SOEGAWA KAGAKU) (697
mg, 4.6 mmol) was suspended in anhydrous THF (3 ml), a trace amount of
iodine was added, and then 1,2-diiodoethane (652 mg, 2.3 mmol) was added,
and stirring was continued for 1 hour at 0 degrees C. While cooling with
ice, a solution of 5-(4-chlorobenzyl)-1,1-dimethyl-4-spiro[2.4]heptanone
(Compound (IV), X=4-Cl, n=1, R1=H, R2=H, R3=Me, R4=Me
(304 mg, 1.2 mmol) and diiodomethane (316 mg, 1.2 mmol) dissolved in
anhydrous THF (1 ml) was added dropwise over 5 minutes. After stirring
for 30 minutes at 0 degrees C., while cooling with ice, 10% aqueous
solution of sodium hydroxide (1 ml) was added dropwise and portionwise,
and then stirring was continued further for 1.5 hours at 0 degrees C.
Solid materials were removed by filtration with aspiration, and
extraction was made with ethyl acetate. The organic layer was washed with
water, saturated brine, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and a crude title
compound was obtained.

[0181] Under nitrogen flow, 60% sodium hydride (1.75 g, 43.8 mmol) was
washed with hexane, and then suspended in anhydrous THF (15 ml), and then
while heating under reflux an anhydrous THF (5 ml) solution of the crude
product of 2-(2-bromoethyl)-5-(4-chlorobenzyl)cyclopentanone (Compound
(V), X=4-Cl, n=1, R1=H, R2=H, R3=H, R4=H, Z1=Br)
(4.61 g, 14.6 mmol) was added dropwise over 10 minutes, and then heated
under reflux for 6 hours. The reaction solution was poured into an iced
water, and extracted with ethyl acetate. The organic layer was washed
with a saturated brine, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resultant crude
product was purified by a silica gel column chromatography (eluent,
hexane-ethyl acetate, 19:1) to obtain the title compound.

[0187] Under nitrogen flow, 60% sodium hydride (345 mg, 8.6 mmol) was
washed with hexane, and then suspended in DMSO (4 ml), and then
trimethylsulfoxonium bromide (1.49 g, 8.6 mmol) was added. After stirring
at room temperature for 5 minutes, a DMSO (3 ml) solution of a crude
2-(4-chlorobenzyl)-5-isopropylidenecyclopentanone (Compound (IX), X=4-Cl,
n=1, R6=Me, R7=Me) (2.15 g, 8.6 mmol) obtained above was added,
and stirring was continued at room temperature for 6 hours. The reaction
solution was poured into an iced water, and extracted with ethyl acetate.
The organic layer was washed with water, saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under reduced
pressure, and the resultant crude product was purified by a silica gel
column chromatography (eluent, hexane-ethyl acetate 19:1) to obtain the
title compound.

[0190] Under nitrogen flow, 60% sodium hydride (1.54 g, 38.7 mmol) was
washed with hexane, and then suspended in dimethyl carbonate (18 ml), and
then 10 drops of dehydrated methanol was added. While heating under
reflux, a dimethyl carbonate (Compound (XVI), R8=Me, Y=OMe) (8 ml)
solution of spiro[2.4]-4-heptanone (Compound (XV), R1=H, R2=H,
R3=H, R4=H)(2.84 g, 25.8 mmol) was added dropwise over 10
minutes (total amount of dimethyl carbonate used was 23.72 g, 258 mmol),
and then heating under reflux was continued for 3.5 hours. The reaction
solution was poured into an iced water, and extracted with ethyl acetate.
The organic layer was washed with water, saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under reduced
pressure, the resultant crude product was purified by a silica gel column
chromatography (eluent, hexane-ethyl acetate=9:1) to obtain the crude
title compound.

[0193] Under nitrogen flow, 60% sodium hydride (270 mg, 6.8 mmol) was
washed with hexane, and then suspended in anhydrous DMF (3 ml), and then
while cooling with ice an anhydrous DMF (3 ml) solution of
4-oxaspiro[2.4]heptane-5-carboxylic acid methyl ester (Compound (XIV),
X=4-F, n=1, R1=H, R2=H, R3=H, R4=H, R8=Me) (758
mg, 4.5 mmol) was added dropwise over 5 minutes. After stirring at 0
degrees C. for 5 minutes, 4-fluorobenzyl bromide (665 mg, 4.5 mmol) was
added, and stirring was continued for 3 hours at 80 degrees C. The
reaction solution was poured into an iced water, and extracted with ethyl
acetate. The organic layer was washed with water, saturated brine, and
dried over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and a crude title compound was obtained.

[0196] The crude methyl
5-(4-fluorobenzyl)-4-oxaspiro[2.4]heptane-5-carboxylate obtained above
(Compound (XII), X=4-F, n=1, R1=H, R2=H, R3=H, R4=H,
R8=Me) (1.18 g, 4.3 mmol) was dissolved in 2-propanol (3 ml), and a
solution of sodium hydroxide (269 mg, 6.4 mmol) in water (1 ml) was
added, and stirring was continued at 60 degrees C. for 5 hours. The
reaction solution was poured into an iced water, and extracted with ethyl
acetate. The organic layer was washed with water, saturated brine, and
dried over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, the resultant crude product was purified by a silica
gel column chromatography (eluent, hexane-ethyl acetate=9:1) to obtain
the title compound.

[0199] Under nitrogen flow, 60% sodium hydride (1.64 g, 41.0 mmol) was
washed with hexane, and then suspended in anhydrous DMF (2 ml) solution,
and then while cooling with ice an anhydrous DMF (10 ml) solution
(dissolved with heating) of methyl
3-(4-chlorobenzyl)-2-oxocyclopentanecarboxylate (Compound (VII), X=4-Cl,
n=1, R1=H, R2=H, R3=H, R4=H, R5=Me) (10 g, 0.37
mmol) was added dropwise over 30 minutes. The DMF solution was washed
with anhydrous DMF (3 ml), and added dropwise to the reaction solution.
At room temperature, stirring was continued for about 1 hour, bromoethyl
methyl ether (Compound (XVII), R1=H, R2=H, R3=H,
R4=H, Z4=Br, R9=Me) (6.25 g, 45.0 mmol) was added, and
stirring was continued at 70 degrees C. for 7 hours. The reaction
solution was poured into an iced water, made acidic with a dilute
hydrochloric acid, and extracted with ethyl acetate. The organic layer
was washed with a saturated brine, and the solvent was distilled off
under reduced pressure.

[0200] The resultant crude product was purified by a silica gel column
chromatography (eluent, hexane-ethyl acetate=10:1-7:1) to obtain the
title compound.

[0207] The following Compounds (IV) were synthesized by the methods
analogous to the abovementioned Production Examples 6 to 9. The
structures of respective compounds are listed in Table 24. The
Characteristics of the respective compounds are listed in Table 24.

[0208] The following Compounds (XII) were synthesized by the methods
analogous to the abovementioned Production Example 8. The structures of
respective compounds are listed in Table 26. The Characteristics of the
respective compounds are listed in Table 27.

[0209] The followings are Formulation Examples and Experiment Examples, in
which carriers (diluents) and auxiliary agents, as well as the mixing
ratio thereof for active ingredients may vary within a wide range.
"Parts" in each Formulation Example means "parts by weight".

Formulation Example 1

Wettable Formulation

[0210] Compound (1-1) 50 parts

[0211] Lignin sulfonate 5 parts

[0212] Alkyl sulfonate 3 parts

[0213] Diatomaceous earth 42 parts

were ground and mixed to form a wettable formulation, which was used as
being diluted in water.

Formulation Example 2

Powder Formulation

[0214] Compound (I-1) 3 parts

[0215] Clay 40 parts

[0216] Talc 57 parts

were ground and mixed, and used as a dusting formulation.

Formulation Example 3

Granule Formulation

[0217] Compound (I-1) 5 parts

[0218] Bentonite 43 parts

[0219] Clay 45 parts

[0220] Lignin sulfonate 7 parts

were mixed uniformly, combined with water and further kneaded, and
subjected to an extruding granulator to obtain a granule, which was dried
and used as a granule formulation.

Formulation Example 4

Emulsion Formulation

[0221] Compound (I-1) 20 parts

[0222] Polyoxyethylene alkylaryl ether 10 parts

[0223] Polyoxyethylene sorbitan monolaurate 3 parts

[0224] Xylene 67 parts

were mixed and dissolved uniformly to obtain an emulsion.

Experimental Example 1

Cucumber Gray Mold Preventing Effect Assay

[0225] To a cucumber (variety: SHARP1) plant in its cotyledon phase grown
using a square plastic pot (6 cm-square) was used to cultivate, a
wettable formulations such as Formulation Example 1 which was diluted and
suspended in water at a certain concentration (500 mg/L) was sprayed at a
rate of 1,000 L/ha. The sprayed leaves were air-dried, and loaded with a
paper disc (8 mm in diameter) soaked with a spore suspension of a
cucumber gray mold microorganism, and kept at 20 degrees C. and a high
humidity. 4 Days after inoculation, the cucumber gray mold severity was
investigated, and the protective value was calculated by the following
equation.

[0227] In an analogous assay in which modification was made to a certain
concentration (25 mg/l), comparison was made with Compound (A) in which a
cyclopropyl ring was fused with a cyclopentane ring described in Patent
Literature 13 (JP-A 11-80126), and it was revealed that the inventive
Compound (I-1) exhibited a higher activity.

[0228] Onto a wheat plant (variety: NORIN No. 61) grown to the two-leaf
phase using a square plastic pot (6 cm-square), a wettable formulations
such as Formulation Example 1 which was diluted and suspended in water at
a certain concentration (500 mg/L) was sprayed at a rate of 1,000 L/ha.
The sprayed leaves were air-dried, and inoculated with wheat leaf rust
microorganism's spore (adjusted at 200 spores/vision, Gramin S was added
at 60 ppm) by spraying, and kept at 25 degrees C. and a high humidity for
48 hours. Thereafter, the plant was kept in a greenhouse. 9 to 14 days
after inoculation, the wheat leaf rust severity was investigated, and the
protective value was calculated by the following equation.

TABLE-US-00030
TABLE 30
Disease index Leaf rust damage scale by Peterson
0 No damage
0.5 Less than 1%
1 1% or higher and less than 5%
2 5% or higher and less than 10%
3 10% or higher and less than 30%
4 30% or higher and less than 50%
5 50% or higher

[0230] Onto a wheat plant (variety: NORIN No. 61) grown to the two-leaf
phase using a square plastic pot (6 cm-square), a wettable formulations
such as Formulation Example 1 which was diluted and suspended in water at
a certain concentration (500 mg/L) was sprayed at a rate of 1,000 L/ha.
The sprayed leaves were air-dried, and splashed with wheat powdery mildew
microorganism's spore, and thereafter kept in a greenhouse. 14 Days after
inoculation, the wheat powdery mildew severity was investigated, and the
protective value was calculated by the following equation.

TABLE-US-00031
TABLE 31
Disease index % Area of disease
0 No disease
0.5 % Area of disease of Less than 1%
1 % Area of disease of 1% or higher and less than 5%
2 % Area of disease of 5% or higher and less than 10%
3 % Area of disease of 10% or higher and less than 30%
4 % Area of disease of 30% or higher and less than 50%
5 % Area of disease of 50% or higher

[0232] 2 mg of a test compound was dissolved in 18 microliter of DMSO, and
applied to 1 g of wheat seeds in a vial. On the next day, 10 seeds/pot
were seeded to 1/10000 a pots, which were cultivated in a greenhouse with
supplying water underneath. In the greenhouse, a diseased wheat seedling
as an inoculant was placed, whereby keeping an infectious condition all
the time. 7, 14, 28 and 56 days after seeding, severity was investigated
by the following criteria, and the protective value was calculated by the
following equation.

TABLE-US-00032
TABLE 32
Disease index % Area of disease
0 No disease
0.5 % Area of disease of Less than 1%
1 % Area of disease of 1% or higher and less than 5%
2 % Area of disease of 5% or higher and less than 10%
3 % Area of disease of 10% or higher and less than 30%
4 % Area of disease of 30% or higher and less than 50%
5 % Area of disease of 50% or higher

Assay for Antimicroorganism Effect on Various Pathogenic Microorganism and
Hazardous Microorganisms

[0239] In this Experiment Example, a method described below was employed
to test the antimicroorganism effects of inventive compounds on various
pathogenic molds for plants and hazardous microorganism for industrial
materials.

<Testing Methods>

[0240] 10 mg of each of inventive compounds was weighed and dissolved in 2
ml of dimethyl sulfoxide. 0.6 ml of this solution was added to 60 ml of a
PDA medium (potato dextrose agar medium) and at about 60 degrees C.,
which was mixed thoroughly in a 100-ml conical flask, and poured into a
dish, where it was solidified, whereby obtaining a plate medium
containing the inventive compound at the final concentration of 50 mg/l.
On the other hand, a subject microorganism previously cultured on a plate
medium was cut out using a cork borer whose diameter was 4 mm, and
inoculated to the drug-containing plate medium described above. After
inoculation, the dish was grown at the optimum growth temperature for
respective microorganism (for this growth temperature, see, for example,
LIST OF CULTURES 1996 microorganisms 10th edition, Institute for
Fermentation (foundation)) for 1 to 3 days, and the microorganism growth
was measured as a diameter of its flora. The growth degree of the
microorganism on the drug-containing plate medium thus obtained was
compared with the growth degree of the microorganism in the untreated
group, and % mycelial extension inhibition was calculated by the
following equation.

[0277] 36 mg of a test compound was dissolved in 3.6 ml of DMSO, and
applied to 180 g of rice seeds in a vial. After soaking the seeds and
promoting germination, the seeds were seeded to seedling boxes at a rate
of 180 g/box, allowed to germinate in the seedling boxes, and then
cultivated in a greenhouse at 35 degrees C. 20 Days after seeding, the
plant height of the seedlings in each treatment group was surveyed in 10
locations, and the % plant height suppression was calculated by the
following Equation 6.

[0286] A 5-benzyl-4-azolylmethyl-4-spiro[2.4]heptanol derivative
represented by Formula (I) according to the invention is not only useful
as an active ingredient of an agro-horticultural fungicide, but also
useful as a plant growth regulator which regulates the growth of a
variety of crops and horticultural plants whereby exhibiting
yield-increasing effects or quality-improving effects, as well as an
industrial material protecting agent which protects an industrial
material from a wide range of hazardous microorganisms which invades such
materials.

Patent applications by Atsushi Ito, Tokyo JP

Patent applications by Eiyu Imai, Tokyo JP

Patent applications by Masaru Mori, Tokyo JP

Patent applications by Nobuyuki Kusano, Tokyo JP

Patent applications by Takashi Shimokawara, Tokyo JP

Patent applications by KUREHA CORPORATION

Patent applications in class The nitrogen is double or triple bonded to carbon

Patent applications in all subclasses The nitrogen is double or triple bonded to carbon